media 5783
TRANSCRIPT
-
8/9/2019 Media 5783
1/18
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
ICH Secretariat, c/o IFPMA, 15, chemin Louis-Dunant, P.O. Box 195, 1211 Geneva 20, SwitzerlandTelephone: +41 (22) 338 32 06 Telefax: +41 (22) 338 32 30
E-mail : [email protected] Web site : http://www.ich.org
Quality Implementation Working Group
on Q8, Q9 and Q10
Questions & Answers
Current version
dated October 29, 2009
-
8/9/2019 Media 5783
2/18
In order to facilitate the implementation of the Q8/Q9/Q10 guidelines, the ICH Experts have
developed a series of Q&As:
Q8/Q9/Q10 Q&As
Document History
Code History Date
Q8/Q9/Q10
Q&As
Approval by the ICH Steering Committee under
Step 4
15 April 2009
Q8/Q9/Q10
Q&As
Approved by the ICH Steering Committee under
Step 4 on newly added questions
11 June 2009
Q8/Q9/Q10
Q&As
Correction made to Question 7 of Section 2.2 Real
Time Release Testing
23 July 2009
Q8/Q9/Q10
Q&As
Change Q8(R1) to Q8(R2)
Approved by the ICH Steering Committee under
Step 4 on newly added questions
29 October 2009
-
8/9/2019 Media 5783
3/18
Last Update : October 29, 2009
0
TABLE OF CONTENTS
1. INTRODUCTION.. 1
1.1 For General Clarification... 2
2. QUALITY BY DESIGN TOPICS.. 3
2.1 Design Space.... 3
2.2 Real Time Release Testing 5
2.3 Control Strategy.. 8
3. PHARMACEUTICAL QUALITY SYSTEM.. 9
4. ICH NEW QUALITY GUIDELINES IMPACT ON GMP INSPECTION PRACTICES... 11
5. KNOWLEDGE MANAGEMENT.. 12
6. SOFTWARE SOLUTIONS. 15
-
8/9/2019 Media 5783
4/18
Last Update : October 29, 2009
1
1. INTRODUCTION
This Questions and Answers document (Q&A) refers to the current working procedure of the ICH Q-IWG on implementing the guidelines of
Q8, Q9 and Q10 which have been approved by the ICH Steering Committee.
The benefits of harmonizing technical requirements across the ICH regions can only be reached if the various Q-ICH guidelines are
implemented and interpreted in a consistent way across the three regions. Implementation Working Group is tasked to develop Q&As to
facilitate implementation of existing guidelines.
References
ICH Q8(R2) Pharmaceutical Development
Part I: Pharmaceutical Development
Part II: Annex to Pharmaceutical Development
http://www.ich.org/LOB/media/MEDIA4986.pdf
approved Aug. 2009
approved Nov. 10 2005
approved Nov. 13 2008
ICH Q9 Quality Risk Management
http://www.ich.org/LOB/media/MEDIA1957.pdf
approved Nov. 09 2005
ICH Q10 Pharmaceutical Quality Systems
http://www.ich.org/LOB/media/MEDIA3917.pdf
approved Jun. 04 2008
-
8/9/2019 Media 5783
5/18
Last Update : October 29, 2009
2
Q8/Q9/Q10
Questions and Answers1.1 FOR GENERAL CLARIFICATION
Date of
Approval
Questions Answers
1 June2009
Is the minimal approach accepted by regulators? Yes. The minimal approach as defined in Q8(R2) (sometimealso called baseline or traditional approach) is the
expectation which is to be achieved for a fully acceptable
submission.However the enhanced approach as described in
ICH Q8(R2) is encouraged (Ref. Q8(R2) Appendix 1).
2 Oct.
2009
What is an appropriate approach for process validation using ICHQ8, Q9 and Q10?
The objectives of process validation are unchanged when usingICH Q8, Q9 and Q10. The main objective of process validationremains that a process design yields a product meeting its pre-
defined quality criteria. ICH Q8, Q9 and Q10 provide astructured way to define product critical quality attributes,design space, the manufacturing process and the controlstrategy. This information can be used to identify the type andfocus of studies to be performed prior to and on initialcommercial production batches. As an alternative to thetraditional process validation, continuous process verification[see definition in ICH Q8(R2) glossary] can be utilised in processvalidation protocols for the initial commercial production and for
manufacturing process changes for the continual improvementthroughout the remainder of the product lifecycle.
3 Oct.
2009
How can information from risk management and continuousprocess verification provide for a robust continual improvementapproach under ICH Q8, Q9 and Q10?
Like the product itself, process validation also has a lifecycle(process design, process qualification and ongoing process verification). A risk assessment conducted prior to initialcommercial validation batches can highlight the areas whereparticular focus and data is needed to demonstrate the desiredhigh level of assurance of commercial process robustness.Continual monitoring (e.g., via Continuous Process Verification)
can further demonstrate the actual level of assurance of process
-
8/9/2019 Media 5783
6/18
Last Update : October 29, 2009
3
Date of
Approval
Questions Answers
consistency and provide the basis for continual improvement ofthe product. Quality Risk Management methodologies of ICH Q9can be applied throughout the product lifecycle to maintain astate of process control.
2. QUALITY BY DESIGN TOPICS
Date of
Approval
Questions Answers
1 April
2009
Is it always necessary to have a Design Space (DS) or Real
Time Release (RTR) testing to implement QbD?
Under Quality by Design, establishing a design space or using
real time release testing is not necessarily expected [ICH
Q8(R2), Step 4].
2.1 Design Space
Date of
Approval
Questions Answers
1 April
2009
Is it necessary to study multivariate interactions of all
parameters to develop a design space?
No, the applicant will need to justify the choice of material
attributes and parameters for multivariate experimentation
based on risk assessment and desired operational flexibility.
2 April
2009
Can a design space be applicable to scale-up? Yes, when appropriately justified [additional details see
Q8(R2) Section 2.4.4]. An example of a scale-independentdesign space is provided in the EFPIA Mock P2 document
[EFPIA Mock P2 submission on Examplain: Chris Potter,
Rafael Beerbohm, Alastair Coupe, Fritz Erni, Gerd Fischer,
Staffan Folestad, Gordon Muirhead, Stephan Roenninger,
Alistair Swanson, A guide to EFPIA's "Mock P.2" Document,
Pharm. Tech. (Europe), 18, December 2006, 39-44].
This example may not reflect the full regulatory requirements
for a scale-up.
-
8/9/2019 Media 5783
7/18
Last Update : October 29, 2009
4
Date of
Approval
Questions Answers
3 April2009
Can a design space be applicable to a site change? Yes, it is possible to justify a site change using a siteindependent design space based on a demonstrated
understanding of the robustness of the process and an in depth
consideration of site specific factors, e.g., equipment,
personnel, utilities, manufacturing environment, and
equipment. There are region specific regulatory requirements
associated with site changes that need to be followed.
4 April
2009
Can a design space be developed for single and/or multiple
unit operations?
Yes, it is possible to develop a design space for single unit
operations or across a series of unit operations [see Q8(R2)Section 2.4.3].
5 April
2009
Is it possible to develop a design space for existing products? Yes, it is possible. Manufacturing data and process knowledge
can be used to support a design space for existing products.
Relevant information should be utilised from e.g., commercial
scale manufacturing, process improvement, CAPA and
development data.
For manufacturing operations run under narrow operationalranges in fixed equipment, an expanded region of operation
and an understanding of multi-parameter interactions may
not be achievable from existing manufacturing data alone and
additional studies may be needed to develop a design space.
Sufficient knowledge should be demonstrated and the design
space should be supported experimentally to investigate
interactions and establish parameter/attribute ranges.
6 April
2009Is there a regulatory expectation to develop a design space for
an existing product?
No, development of design space for existing products is not
necessary unless the applicant has a specific need and desires
to use a design space as a means to achieve a higher degree of
product and process understanding. This may increase
manufacturing flexibility and/or robustness.
-
8/9/2019 Media 5783
8/18
-
8/9/2019 Media 5783
9/18
Last Update : October 29, 2009
6
Date of
Approval
Questions Answers
specific analytical procedures on a defined sample size of thefinal product after completion of all processing for a given
batch of that product. Results of real time release testing are
handled in the same manner as end product testing results in
the batch release decision. Batch release involves an
independent review of batch conformance to predefined criteria
through review of testing results and manufacturing records
together with appropriate GMP compliance and quality
system, regardless of which approach is used.2 April
2009
Does real time release testing mean elimination of end
product testing?
Real time release testing does not necessarily eliminate all end
product testing. For example, an applicant may propose RTR
testing for some attributes only or not all. If all CQAs (relevant
for real time release testing) are assured by in-process
monitoring of parameters and/or testing of materials, then end
product testing might not be needed for batch release. Some
product testing will be expected for certain regulatory
processes such as stability studies or regional requirements.3 April
2009
Is a product specification still necessary in the case of RTR
testing?
Yes, product specifications [see ICH Q6A and Q6B] still need
to be established and met, when tested.
4 April
2009
When using RTR testing, is there a need for stability test
methods?
Even where RTR testing is applied, a stability monitoring
protocol that uses stability indicating methods is required for
all products regardless of the means of release testing. [see
ICH Q1A and ICH Q5C].
5 April
2009
What is the relationship between Control Strategy and RTR
testing?
RTR testing, if utilized, is an element of the Control Strategy
in which tests and/or monitoring can be performed as in
process testing (in-line, on-line, at-line) rather than tested on
the end product.
6 April
2009
Do traditional sampling approaches apply to RTR testing? No, traditionally sampling plans for in-process and end-
product testing involve a discrete sample size that represents
the minimal sampling expectations. Generally, the use of RTR
testing will include more extensive on-line/in-line
measurement. A scientifically sound sampling approach should
be developed, justified, and implemented.
-
8/9/2019 Media 5783
10/18
Last Update : October 29, 2009
7
Date of
Approval
Questions Answers
7 April2009
If RTR testing results fail or trending toward failure, can end-product testing be used to release the batch?
No, in principle the RTR testing results should be routinelyused for the batch release decisions and not be substituted by
end-product testing. Any failure should be investigated and
trending should be followed up appropriately. However, batch
release decisions will need to be made based on the results of
the investigations. The batch release decision needs to comply
with the content of the marketing authorisation and GMP
compliance.
8 June2009
What is the relationship between in-process testing and RTRtesting?
In-process testing includes any testing that occurs during themanufacturing process of drug substance and/or finished
product. Real time release testing includes those in-process
tests that directly impact the decision for batch release
through evaluation of Critical Quality Attributes.
9 June
2009
What is the difference between real time release and real
time release testing?
The definition of real time release testing in Q8(R2) is the
ability to evaluate and ensure the acceptable quality of in-
process and/or final product based on process data, which
typically includes a valid combination of measured materialattributes and process controls.
The term Real time release in the Q8(R2), Step 2 document
was revised to Real time release testing in the final Q8(R2)
Part II document to fit the definition more accurately and thus
avoid confusion with batch release.
10 June
2009
Can surrogate measurement be used for RTR testing? Yes, RTR testing can be based on measurement of a surrogate
(e.g., process parameter, material attribute) that has been
demonstrated to correlate with an in process or end product
specification [see ICH Q8(R2); Section 2.5.].
11 Oct.
2009
What is the relationship between RTR testing and Parametric
Release?
Parametric release is one type of RTR testing. Parametric releaseis based on process data (e.g., temperature, pressure, time forterminal sterilization, physicochemical indicator) rather than thetesting of material and/or a sample for a specific attribute.
-
8/9/2019 Media 5783
11/18
-
8/9/2019 Media 5783
12/18
Last Update : October 29, 2009
9
Date of
Approval
Questions Answers
5 Oct.2009
Are product specifications different for minimal versus QbDapproaches?
In principle no, the same product specifications are neededfor minimal and QbD approaches. For a QbD approach, thecontrol strategy may allow achieving the end productspecifications via real time release testing approaches [seeICH Q8(R2), Appendix 1]. Product must meet specification,when tested.
3. PHARMACEUTICAL QUALITY SYSTEM
Date of
Approval
Questions Answers
1 April
2009
What are the benefits of implementing a Pharmaceutical
Quality System (in accordance with ICH Q10)?
The benefits are:
Facilitated robustness of the manufacturing process,
through facilitation of continual improvement through
science and risk-based post approval change processes; Consistency in the global pharmaceutical environment
across regions;
Enable transparency of systems, processes, organisational
and management responsibility;
Clearer understanding of the application of a Quality
System throughout product lifecycle;
Further reducing risk of product failure and incidence of
complaints and recalls thereby providing greaterassurance of pharmaceutical product consistency and
availability (supply) to the patient;
Better process performance;
Opportunity to increase understanding between industry
and regulators and more optimal use of industry and
regulatory resources. Enhance manufacturers and
regulators confidence in product quality;
Increased compliance with GMPs, which builds confidence
-
8/9/2019 Media 5783
13/18
Last Update : October 29, 2009
10
Date of
Approval
Questions Answers
in the regulators and may result in shorter inspections.2 April
2009
How does a company demonstrate implementation of PQS in
accordance with ICH Q10?
When implemented, a company will demonstrate the use of
an effective PQS through its documentation (e.g., policies,
standards), its processes, its training/qualification its
management its continual improvement efforts, and its
performance against pre-defined Key Performance Indicators
[see ICH Q10 glossary on Performance indicator].
A mechanism should be established to demonstrate at a site
how the PQS operates across the product lifecycle, in aneasily understandable way for management, staff and
regulatory inspectors, e.g., a quality manual, documentation,
flowcharts, procedures. Companies can implement a program
in which the PQS is routinely audited in-house (i.e., internal
audit program) to ensure that the system is functioning at a
high level.
3 April
2009
Is it necessary to describe the PQS in a regulatory
submission?
No, however relevant elements of the PQS, such as quality
monitoring system, change control and deviationmanagement may be referenced as part of the control
strategy as supporting information.
4 April
2009
Will there be certification that the PQS is in accordance with
ICH Q10?
No. There will not be a specific ICH Q10 certification
programme.
5 April
2009
How should the implementation of the design space be
evaluated during inspection of the manufacturing site?
Inspection should verify/assess that manufacturing
operations are appropriately carried out within the Design
Space. The inspector in collaboration with the assessor,
where appropriate, should also verify successfulmanufacturing operations under the Design Space and that
movement within the Design Space is managed within the
companys change management system [see ICH Q10,
Section 3.2. Table III].
6 April
2009
What should be done if manufacturing operations run
inadvertently outside of the Design Space?
This should be handled as a deviation under GMP. For
example unplanned one-off excursions occurring as a result
of unexpected events, such as operator error or equipment
failure, would be investigated, documented and dealt with as
-
8/9/2019 Media 5783
14/18
Last Update : October 29, 2009
11
Date of
Approval
Questions Answers
a deviation in the usual way. The results of the investigationmay contribute to the process knowledge, preventive actions
and continual improvement of the product.
7 June
2009
What information and documentation of the development
studies should be available at a manufacturing site?
Pharmaceutical development information (e.g., supporting
information on design space, chemometric model, risk
management,) is available at the development site.
Pharmaceutical development information which is useful to
ensure the understanding of the basis for the manufacturing
process and control strategy, including the rationale forselection of critical process parameters and critical quality
attributes should be available at the manufacturing site.
Scientific collaboration and knowledge sharing between
pharmaceutical development and manufacturing is essential
to ensure the successful transfer to production.
8 June
2009
Can process parameters be adjusted throughout the product
lifecycle?
Process parameters are studied and selected during
pharmaceutical development and monitored during
commercial manufacturing. Knowledge gained could beutilized for adjustment of the parameters as part of continual
improvement of the process throughout the lifecycle of the
drug product (see ICH Q10, Section 3.).
4. ICH NEW QUALITY GUIDELINES IMPACT ON GMP INSPECTION PRACTICES
Date of
Approval
Questions Answers
1 April
2009
How will product-related inspections differ in an ICH Q8, Q9
and Q10 environment?
In the case of product-related inspection (in particular pre-
authorisation) depending on the complexity of the product
and/or process, there could be a need for greater collaboration
between inspectors and assessors for example for the
assessment of development data. The inspection would
normally occur at the proposed commercial manufacturing
-
8/9/2019 Media 5783
15/18
Last Update : October 29, 2009
12
Date of
Approval
Questions Answers
site and there is likely to be greater focus on enhancedprocess understanding and understanding relationships e.g.,
Critical Quality Attribute (CQAs), Critical Process
Parameters (CPPs). It will also extend into the application
and implementation of quality risk management principles,
as supported by the Pharmaceutical Quality System (PQS).
2 April
2009
How will system-related inspections differ in an ICH Q8, Q9
and Q10 environment?
The inspection process will remain similar. However upon
the implementation of ICH Q8, Q9 and Q10, inspections will
have greater focus (but not only) on how the PQS facilitatesthe use of e.g., Quality Risk Management methods,
implementation of design space and change management
[see ICH Q10].
3 Oct.
2009
How is control strategy approved in the application and
evaluated during inspection?
Elements of control strategy submitted in the application will
be reviewed and approved by the regulatory agency.
However, additional elements are subject to inspection (as
described in Q10).
5. KNOWLEDGE MANAGEMENT
Date of
Approval
Questions Answers
1 April
2009
How has the implementation of ICH Q8, Q9, and Q10 changed
the significance and use of knowledge management?
Q10 defines knowledge management as: Systematic
approach to acquiring, analyzing, storing, and disseminatinginformation related to products, manufacturing processes
and components.
Knowledge management is not a system; it enables the
implementation of the concepts described in ICH Q8, Q9 and
Q10.
Knowledge Management is not a new concept. It is always
important regardless of the development approach. Q10
highlights knowledge management because it is expected
-
8/9/2019 Media 5783
16/18
Last Update : October 29, 2009
13
Date of
Approval
Questions Answers
that more complex information generated by appropriateapproaches (e.g., QbD, PAT, real-time data generation and
control monitoring systems) will need to be better captured,
managed and shared during product life-cycle.
In conjunction with Quality Risk Management, Knowledge
Management can facilitate the use of concepts such as prior
knowledge (including from other similar products),
development of design space, control strategy, technology
transfer, and continual improvement across the product lifecycle.
2 April
2009
Does Q10 suggest an ideal way to manage knowledge? No. Q10 provides a framework and does not prescribe how to
implement knowledge management. Each company decides
how to manage knowledge, including the depth and extent of
information assessment based on their specific needs.
3 April
2009
What are potential sources of information for Knowledge
Management?
Some examples of knowledge sources are:
Prior knowledge based on experience obtained from similar
processes (internal knowledge, industry scientific andtechnical publications) and published information
(external knowledge: literature and peer-reviewed
publications);
Pharmaceutical development studies;
Mechanism of action;
Structure/function relationships;
Technology transfer activities;
Process validation studies; Manufacturing experience e.g.,
- Internal and Vendor audits;
- Raw material testing data;
Innovation;
Continual improvement;
Change management activities;
Stability reports;
-
8/9/2019 Media 5783
17/18
Last Update : October 29, 2009
14
Date of
Approval
Questions Answers
Product Quality Reviews/Annual Product Reviews; Complaint Reports;
Adverse event reports (Patient safety);
Deviation Reports, Recall Information;
Technical investigations and/or CAPA reports;
Suppliers and Contractors;
Product history and /or manufacturing history;
Ongoing manufacturing processes information (e.g., trends).
Information from the above can be sourced and shared across
a site or company, between companies and
suppliers/contractors, products and across different
disciplines (e.g., development, manufacturing, engineering,
quality units).
4 April
2009
Is a specific dedicated computerised information management
system required for the implementation of knowledgemanagement with respect to ICH Q8, Q9 and Q10?
No, but such computerised information management systems
can be invaluable in capturing, managing, assessing andsharing complex data and information.
5 June
2009
Will regulatory agencies expect to see a formal knowledge
management approach during inspections?
No. There is no added regulatory requirement for a formal
knowledge management system. However it is expected that
knowledge from different processes and systems will be
appropriately utilised.
Note: formal means: it is a structured approach using a
recognised methodology or (IT-) tool, executing and
documenting something in a transparent and detailedmanner.
-
8/9/2019 Media 5783
18/18